Novel ophthalmic composition and methods of use

ABSTRACT

Described are stable topical formulations useful in the treatment of viral infection, demodex infection and bacterial infection of the eye, and methods of using the compositions for treating viral infection, demodex infection and bacterial infection of the eye.

CROSS-REFERENCE TO RELATED APPLICATIONS

The subject application claims the benefit of U.S. Provisional PatentApplication, Ser. No. 62/187,973, filed Jul. 2, 2015, which isincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Millions of human patients suffer from viral infection or viral wartinfection, demodex infection, fungal or yeast infection, or bacterialinfection of the skin, including skin of the eye, eyelid or periocularregion.

Infections of the eye or eyelid may occur via direct person-to-personskin contact, or indirectly through contaminated surfaces in a publiclyaccessed area, such as a public swimming pool or gymnasium. Exposure tothe infectious agent can occur through minor abrasions and infection ispromoted via maceration of the epithelia. Autoinoculation is common aswell.

Verruca vulgaris, the medical term for wart, serves as an umbrella termfor all warts. Warts can result from viral infections that are mostoften associated with Human Papilloma Virus (HPV) or MolluscumContagiosum Virus (MCV) Non-genital varieties of skin warts occur in 20%of schoolchildren with equal frequency in both sexes.

Viral or viral wart infection, demodex infection, fungal or yeastinfection, or bacterial infection of the eyelids, conjunctiva, cornea,ocular surface or Meibomian glands, can manifest as blepharitis and/orblepharoconjunctivitis or conjunctivitis—an infectious and inflammatorycondition of the eyelid or ocular surface.

Blepharoconjunctivitis and blepharitis are commonly encounteredconditions affecting approximately 15% of the population, and representan inflammatory, infectiouis or mixe condition of the eyelids.Blepharitis may involve the dermis, eyelashes, tarsal conjunctiva,mucocutaneous junction or meibomian glands and is most often caused bygram positive bacterial infection, such as Stapylococcus,Corynebacterium, and Pripionibacterium species. However, other agentscausing blepharitis include viral, demodex (mite), or yeast infections,seborrhea, rosacea, and hormonal dysregulation.

Left untreated, blepharitis may cause dry eye exacerbation, loss ofcilia, corneal ulceration, and impart increased risk of endophthalmitisafter cataract surgery. For facility in understanding, it is commonlycompartmentalized into inflammation affecting the structures of theanterior, posterior lid margin or both.

Anterior blepharitis most commonly presents as anterior lid and lashcrusting with or without the presence of collarettes. Othermanifesations may also include skin or lash flaking associated withseborrhea or angular inflammation particular to Moraxella or virus.

Posterior blepharitis is also commonly referred to as meibomian glanddisease. Meibomian glands are responsible for the release of lipids intothe tear film, effectively mitigating evaporative tear loss. Besides thechronic irritation, inflammation and erythema common to all blepharitis,the posterior variant may further be characterized by inspissation ofthe meibomian glands, keratinization of orifices, telangiectasia, andposterior margin lid thickening. Bacterial lipases stemming from theocular flora may also act upon meibomian secretions creating free fattyacids which further disturb the ocular surface.

Current treatments for bacterial, demodex, fungal/yeast, and viralinfections, including warts and ophthalmic conditions such asblepharitis, can be ineffective in that they treat only a subset of thecausative agent of the infection. Many of the current treatmentsincorporate undesirable ingredients, such as steroids or otherpotentially harmful components.

A recent discovery by Capriotti, et al., has disclosed compositionscomprising an iodophor such as povidone-iodine (PVP-I), as an activeingredient, and dimethyl sulfoxide (DMSO) were shown to be useful fortreating fungal infections of the skin and nails. See, e.g., USPublication No. US201410205559 (Capriotti '559), which is incorporatedherein by reference in its entirety.

Although a variety of organic solvents, including dimethyl sulfoxide(DMSO), are known to enhance the percutaneous absorption of certainmedicaments, it has been long-accepted in the pharmaceutical arts thatDMSO enhances penetration for small molecules or low molecular weight(LMW) compounds or drugs, only, and was not expected to enhancepenetration of high molecular weight (HMW) compounds greater than about10,000 Daltons, such as polymers, e.g., povidone-iodine. DMSO has onlyrecently, and unexpectedly, been demonstrated to enhance penetration ofpovidone-iodine (PVP-I). PVP-I preparations range in molecular weightsfrom 1,000 to 1,000,000 or more. Topical pharmaceutical compositionshave been approved using only PVP grades K29-32. One acceptable PVPgrade is PVP K30, which has a MW of 30,000 to 60,000 daltons (average MWof about 40,000 daltons). Accordingly, prior to the teachings ofCapriotti '559, one skilled in the art would not employ DMSO in atopical pharmaceutical composition to enhance skin penetration of largemolecules, polymers or high-molecular weight substances such as PVP-I.

Moreover, DMSO was understood and accepted in the art to be toxic to theeye and was not considered to be an acceptable ingredient in acomposition intended for topical administration to the eye or periocularregion. Therefore, not only was DMSO generally recognized as beingunacceptable for use as a penetration enhancer for high molecular weightpolymeric compounds, such as povidone-iodine, DMSO was particularlyavoided as an ingredient for use in ophthalmic preparations, andespecially avoided as an ingredient for topical ophthalmic preparations.

Further, although gel formulations comprising povidone-iodine and DMSOwere mentioned, generally, in Capriotti '559 and related publications,it was discovered that certain formulations comprising povidone-iodine,DMSO, and a gelling agent were not stable for a sufficient period oftime to provide a viable pharmaceutical product having an acceptableshelf-life. Only when particular amounts of povidone-iodine werecombined with particular amounts of DMSO and particular amounts ofgelling agent was stability observed to be sufficient to provide aviable pharmaceutically acceptable product having an acceptable andapprovable shelf-life.

Therefore, it was previously unknown that topical ophthalmic gelformulations comprising povidone-iodine (PVP-I) and DMSO, with a gellingagent, could be made having pharmaceutically acceptable properties andutility. Specifically, the subject topical ophthalmic formulationcomprises DMSO, which has heretofore not been used for ophthalmicpreparations due to the expected toxicity of DMSO to the eye.

Neither were ophthalmic preparations known to contain above 2.0% gellingagent, such as hydroxyethylcellulose (HEC). The subject formulation istherefore unexpectedly effective and stable, making it useful intreating certain viral, demodex, fungal/yeast, or bacterial infectionsmanifesting as ophthalmic conditions (e.g., blepharitis,blepharoconjunctivitis, viral conjunctivitis, bacterial conjunctivitis,keratitis, or the like.)

Thus, the current invention is a significant advance in the art, anddiscloses the surprising and unexpected discovery that a topical gelcomposition comprising particular ingredients, namely, PVP-I, DMSO, anda gelling agent, in particular concentration combinations, can provideadvantageous and unexpected results in the treatment of infection of theeye such as blepharitis or other eye conditions.

SUMMARY OF THE INVENTION

The present invention concerns a topical gel composition comprising aniodophor, a penetration enhancer, and a gelling agent, wherein thecomposition is particularly effective in treating viral, demodex,fungal/yeast, or bacterial infection that can cause warts or eyeconditions, such as blepharitis. Thus, the subject invention furthercomprises a method of treating viral, demodex, fungal/yeast, orbacterial infection using a topical gel composition as disclosed herein.The composition can further comprise optional pharmaceuticallyacceptable excipients or solvents or co-solvents.

A composition of the subject invention preferably comprises activepharmaceutical ingredient (API) approved by the United States Food andDrug Administration (FDA) as acceptable for use in a pharmaceuticalpreparation. A preferred composition of the invention further comprisesinactive ingredients or excipients that are FDA-approved for topicaladministration. An FDA-approved API or inactive ingredient or excipientis referred to herein as “pharmaceutically acceptable.” Accordingly, atopical composition, formulation, or preparation of the subjectinvention comprising a pharmaceutically acceptable API, inactiveingredient or excipient is referred to herein as a “pharmaceuticallyacceptable” topical composition.

Similarly, an ophthalmic composition of the subject invention comprisingFDA-approved active or inactive ingredients acceptable for use in anophthalmic preparation, is referred to herein as a “pharmaceuticallyacceptable ophthalmic composition,” or “ophthalmically acceptable”composition, and comprises an API, an excipient, or a solvent which is“pharmaceutically acceptable” for ophthalmic use.

More particularly, the subject invention relates to a stable topicalcomposition comprising an iodophor having a molecular weight of greaterthan 10,000 Daltons, e.g. povidone-iodine, such as povidone-iodine K30,dimethyl sulfoxide (DMSO), and a gelling agent, and optional additionalpharmaceutically or ophthalmically acceptable excipients or solvents orco-solvents.

A composition of the subject invention can be useful in a method fortreating viral infection or viral wart infection, demodex infection,fungal or yeast infection, or bacterial infection of the eye, eyelids,conjunctiva, cornea, ocular surface, Meibomian glands, or periocularregion.

A topical gel composition of the subject invention is unexpectedlyhighly stable at room temperature in the presence of aqueous oranhydrous ingredients.

A topical ophthalmic gel composition of the subject invention cancomprise about 0.1% to about 1.5% povidone-iodine (PVP-I); about 30% toabout 99% dimethyl sulfoxide (DMSO); and about 1% to about 10% gellingagent. The topical gel composition of the invention unexpectedlyexhibits greater efficacy in treating skin infection or blepharitis,compared to a liquid composition substantially free of a gelling agentand comprising about 0.1% to about 1.5% povidone-iodine and about 30% toabout 99% DMSO.

A preferred topical ophthalmic gel composition comprises about 0.15% to1.5% povidone-iodine (PVP-I). A more preferred composition can compriseabout 0.25% PVP-I to 0.5% PVP-I. The FDA has approved the topical use ofPVP-I having a MW which averages 40,000. Accordingly, a PVP-I grade ofK30 is preferred for use in the subject composition.

A preferred topical ophthalmic gel composition comprises about 30% toabout 99% DMSO. A more preferred composition can comprise about 30% toabout 70% DMSO. A most preferred composition of the invention comprisesabout 40% to about 49% DMSO, and even more preferably, about 44% DMSO.

A preferred topical ophthalmic gel composition comprises about 2% toabout 5% gelling agent. A more preferred composition can comprise about3% gelling agent.

A particularly useful topical ophthalmic gel composition which has beenprepared for testing comprises 0.25% PVP-I; 44% DMSO; 3%hydroxyethylcellulose; and aqueous solvent, q.s. 100%. A preferredaqueous solvent is water or aqueous isotonic solution.

A gelling agent useful for preparing a topical ophthalmic gelcomposition of the invention can include, as is well known in the art,gum, agar, carrageenan, petrolatum, or a cellulosic polymer or the like.One preferred cellulosic polymer useful as a gelling agent ishydroxyethyl cellulose. An alternative cellulosic polymer gelling agentis hydroxymethyl cellulose.

A topical ophthalmic gel composition of the invention preferablycomprises povidone-iodine, or PVP-I having an average molecular weightgreater than 10,000. More preferably, the composition of the inventioncomprises PVP-I having an average molecular weight between about 20,000to about 1,000,000. One preferred embodiment comprises PVP-I having anaverage molecular weight between about 30,000 to about 60,000, orgreater. Each of the PVP-I ingredients referred to herein means a “highmolecular weight PVP-I,” or “HMW PVP-I.”

The topical ophthalmic gel composition is ophthalmically acceptable,comprising one or more ophthalmically acceptable ingredients. Theophthalmic gel composition embodiments described herein canadvantageously can exhibit greater efficacy in treating infectiousconditions of the eye or eyelid, compared to a liquid compositionsubstantially free of a gelling agent (or a gelling agent atconcentrations below those required for forming a gel) and comprisingabout 0.1% to about 10% povidone-iodine and about 30% to about 99% DMSO.

A most preferred topical ophthalmic gel composition comprises apharmaceutical grade povidone-iodine at a range of 0.15% to 0.5%;greater than 30% DMSO up to 90% DMSO; and a gelling agent at a range of2.5% to 5%. All percentages are w/w unless otherwise specified. Thismost preferred composition can also include a co-solvent, such aspolyethylene glycol (PEG). This most preferred composition isunexpectedly stable and efficacious for treating certain eye infections.

A preferred embodiment of the composition comprises a solution, and moreparticularly, a gel solution, wherein the povidone-iodine is dissolvedor solubilized in the final composition. Preferably, the subjectcomposition is not an emulsion or suspension of particulates ofingredients in the gel or final composition.

Preferred embodiments of a topical gel composition of the invention arefree of any additional API or anti-inflammatory drug, such as a steroid,e.g., corticosteroid, or non-steroidal anti-inflammatory drug (NSAID).Thus, a composition of the invention can be described as steroid-free,NSAID-free, steroid-free and NSAID-free, or anti-inflammatory-free. Acomposition of the invention is advantageously useful for treatment ofthe described ophthalmic conditions without an anti-inflammatory,without a steroid, or without an NSAID present in the composition.

One preferred embodiment of a composition of the invention is a stableophthalmically acceptable gel composition comprising

-   -   0.15% to 1.5% povidone-iodine (PVP-I);    -   30% to 97% dimethyl sulfoxide (DMSO);    -   2.5% to 5% hydroxyethylcellulose; and    -   water or isotonic co-solvent;        wherein, the composition is formulated as a topical ophthalmic        gel, free of additional anti-inflammatory drug, or        anti-inflammatory-free.

One preferred embodiment of a composition of the invention is a stable,ophthalmically acceptable gel composition comprising

-   -   0.15% to 1.5% povidone-iodine (PVP-I);    -   30% to 97% dimethyl sulfoxide (DMSO);    -   2.5% to 5% hydroxyethylcellulose; and    -   water or isotonic co-solvent;        wherein, the composition is formulated as a topical ophthalmic        gel, free of steroid.

One preferred embodiment of a composition of the invention is a stable,ophthalmically acceptable gel composition comprising

-   -   0.15% to 1.5% povidone-iodine (PVP-I);    -   30% to 97% dimethyl sulfoxide (DMSO);    -   2.5% to 5% hydroxyethylcellulose; and    -   water or isotonic co-solvent;        wherein, the composition is formulated as a topical ophthalmic        gel, free of corticosteroid.

One preferred embodiment of a composition of the invention is a stable,ophthalmically acceptable gel composition comprising

-   -   0.15% to 1.5% povidone-iodine (PVP-I);    -   30% to 97% dimethyl sulfoxide (DMSO);    -   2.5% to 5% hydroxyethylcellulose; and    -   water or isotonic co-solvent;        wherein, the composition is formulated as a topical ophthalmic        gel, free of NSAID.

A method according to the subject invention comprises, generally, one ormore as-needed topical administrations or topical applications of atopical ophthalmic gel composition of the invention, namely, a topicalcomposition comprising an iodophor, DMSO, and a gelling agent, to thesite, until the ophthalmic infection is eliminated, or is substantiallyinhibited. In a preferred method, the subject gel composition isadministered directly to the site of the infection as needed (PRN),preferably at least once per day (QD), or more preferably at least twotimes per day (BID) until results are seen, typically for about oneweek, up to about 24 weeks. Advantageously, the composition of thesubject invention can be administered directly to the eye or periocularregion and presents no toxicity to the eye.

A preferred embodiment of the invention comprises a method of treatingan infectious condition of the eye or eyelid, comprising applying aneffective amount of a stable, topical ophthalmic gel composition to asite of the infection to reduce or eliminate the infection.

The method of the invention can be useful in treating blepharitis,conjunctivitis, corneal ulcer, HSV keratitis, conjunctival neoplasia, ACinflammation, post-operative endophthalmitis, and endophthalmitis afterintravitreal or intracameral injection, which is caused by or associatedwith one or more infectious agents such as bacteria, demodex, fungus oryeast, or virus.

DETAILED DESCRIPTION OF THE INVENTION

The present invention concerns a topical gel composition comprising anantiseptic agent, a penetration enhancer, and a gelling agent.Preferably, the composition comprises povidone-iodine as the antisepticagent, dimethylsulfoxide (DMSO) as the penetration enhancer, and acellulosic gelling agent, such as hydroxyethylcelluose (HEC). Thecomposition can, optionally, further comprise a lubricant or co-solvent,or other pharmaceutically or ophthalmically acceptable excipients. Forexample, a composition for treating an ophthalmic condition, such asblepharitis can include an ophthalmically acceptable excipient.

The subject composition is surprisingly useful for the treatment ofviral, demodex, fungal/yeast or bacterial infection of the eye, eyelids,conjunctiva, cornea, ocular surface and Meibomian glands, which cancause blepharitis.

A specific but non-limiting example of a formulation of the inventionproviding a useful pharmaceutical preparation comprises solid PVP-Idissolved in DMSO with one or additional co-solvents in solution andprepared as a gel or semi-solid.

In another embodiment, DMSO can be added to aqueous solutions of PVP-I.In an example, DMSO can be present as a co-solvent with water in therange of 10%-99%. One embodiment of such a formulation can include arange of excipients such as water, or sodium chloride, sodium dihydrogenphosphate monohydrate, disodium hydrogen phosphate anhydrous and water,as well as other aqueous solutions or isotonic buffers known to thoseskilled in the art.

Percentages set forth herein are (w/w), with respect to the specifiedcomponent in the overall composition, unless otherwise indicated. Forexample, a composition comprising 1% PVP-I and 45% DMSO has 1% PVP-I byweight, with respect to the total composition.

In an embodiment, a composition comprises povidone-iodine in the rangeof about 0.01% to about 15%. In another embodiment, a compositioncomprises povidone-iodine in the range between 0.05% and 12.5%. Inanother embodiment, a composition comprises povidone-iodine in the rangebetween 0.05% and 10.0%. In another embodiment, a composition comprisespovidone-iodine in the range between 0.1% and 10.0%. In anotherembodiment, a composition comprises povidone-iodine in the range between0.1% and 1.0%. In another embodiment, a composition comprisespovidone-iodine in the range between 0.15% and 1.5 5%. In anotherembodiment, a composition comprises povidone-iodine in the range between0.25% and 0.5%.

In an embodiment, a composition comprises povidone-iodine of about0.01%, about 0.05%, about 0.10%, about 0.15%, about 0.20%, about 0.25%,about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%,about 0.85%, about 0.90%, about 0.95%, about 1.00%, about 1.1%, about1.2%, about 1.3%, about 1.4%, about 1.5%, or any range determinable fromthe preceding percentages. All percentages are expresses as w/w unlessotherwise specified.

In an embodiment, a composition comprises DMSO and PVP-I. In anembodiment, a composition consists essentially of DMSO and PVP-I and agelling agent in an aqueous or anhydrous diluent. In an embodiment, acomposition consists of DMSO and PVP-I and a gelling agent and aco-solvent in an aqueous or anhydrous diluent. In an embodiment, acomposition is anhydrous. In an embodiment, a composition issubstantially anhydrous. In an embodiment, a composition comprises ameasurable amount of water.

In an embodiment, DMSO, e.g., anhydrous DMSO, is used in a composition.In an embodiment, substantially anhydrous DMSO is used in a composition.It will be understood by one of skill in the art that DMSO can beproduced and/or obtained in differing grades, and that one of thevariables among DMSO preparations of different grades is the watercontent. By way of example, DMSO may be completely anhydrous (alsoreferred to herein simply as “anhydrous”), substantially anhydrous, ormay contain water to a measurable degree. It will be understood that theamount of measurable water in a DMSO preparation may vary based onlimitations of the instrumentation and techniques used to make suchmeasurements.

In an embodiment, DMSO that is not completely anhydrous may besubstantially anhydrous and contain water at a level below levels ofdetectability. In an embodiment, DMSO that is not completely anhydrousmay contain water, wherein the water content is about at least 0.01%,about at least 0.02%, about at least 0.03%, about at least 0.04%, aboutat least 0.05%, about at least 0.06%, about at least 0.07%, about atleast 0.08%, about at least 0.09%, about at least 0.1%, about at least0.2%, about at least 0.3%, about at least 0.4%, about at least 0.5%,about at least 0.6%, about at least 0.7%, about at least 0.8%, about atleast 0.9%, about at least 1.0%, about at least 1.5%, about at least2.0%, about at least 2.5%, about at least 5%, about at least 7.5%, aboutat least 10%, about at least 12.5%, or greater. It will be understoodthat DMSO may contain one or more other impurities in addition to water.

In an embodiment, a composition comprises at least one of United StatesPharmacopeial Convention (USP) grade DMSO, Active PharmaceuticalIngredient (API) grade DMSO, analytical grade DMSO, and AmericanChemical Society (ACS) Spectrophotometric grade DMSO. In an embodiment,a composition comprises DMSO having <0.1% water by KF titrationand >99.9% determined on an anhydrous basis.

As set forth above, the percent amount of DMSO in a composition isdescribed in a weight-to-weight (w/w) ratio with respect to one or moreother components of the composition, unless otherwise indicated. In anembodiment, the weight percent DMSO is the balance of the weight percentafter addition of PVP-I. By way of a non-limiting example, a compositionmay comprise 1 weight percent (1%) PVP-I and 99 weight percent (99%)DMSO. It will be understood that in the foregoing example, the DMSOcomponent of the composition may be completely anhydrous, substantiallyanhydrous, or may contain water to a measurable degree. In anembodiment, the weight percent DMSO is the balance of the weight percentafter addition of PVP-I and any other components (e.g., co-solvent,water, additional active ingredient, etc.). In an embodiment, the weightpercent DMSO is the balance of the weight percent after addition ofiodophor and other components, if any. In an embodiment, the weightpercent penetrant in a composition is the balance of the weight percentafter addition of iodophor and other components, if any.

In an embodiment, a composition comprises DMSO in the range of 30% to99.99%. In an embodiment, a composition comprises DMSO in the range of35% to 99.99%. In another embodiment, a composition comprises DMSO inthe range of 40% and 99.9%. In another embodiment, a compositioncomprises DMSO in the range of 30% and 97%. In another embodiment, acomposition comprises DMSO in the range of 35% and 75%. In anotherembodiment, a composition comprises DMSO in the range of 40% and 50%. Inanother embodiment, a composition comprises DMSO in the range of 40% and49%. In another embodiment, a composition comprises DMSO in the range of43% and 45%. In another embodiment, a composition comprises DMSO at 44%.

In an embodiment, a composition comprises gelling agent in the range ofgreater than 2%. In an embodiment, a composition comprises gelling agentin the range of 2.1% to 10%. In another embodiment, a compositioncomprises gelling agent in the range of 2.5% and 5.0%. In anotherembodiment, a composition comprises gelling agent in the range of 2.5%and 4%. In another embodiment, a composition comprises about 2.5% toabout 3.5% gelling agent. In another embodiment, a composition comprises3% gelling agent.

In an embodiment, a composition comprises a co-solvent in the range of1% to 99.99%. In another embodiment, a composition comprises aco-solvent in the range of 5% and 99.9%. In another embodiment, acomposition comprises a co-solvent in the range of 10% and 99.9%. Inanother embodiment, a composition comprises a co-solvent in the range of20% and 99.9%. In another embodiment, a composition comprises aco-solvent in the range of 30% and 99.9%. In another embodiment, acomposition comprises a co-solvent in the range of 40% and 99.9%. Inanother embodiment, a composition comprises a co-solvent in the range of50% and 99.9%. In another embodiment, a composition comprises aco-solvent in the range of 60% and 99.9%. In another embodiment, acomposition comprises a co-solvent in the range of 70% and 99.9%. Inanother embodiment, a composition comprises a co-solvent in the range of80% and 99.9%, and in yet another embodiment, between 90% and 99.9%.

In an embodiment, a composition comprises a co-solvent at about 1%. Inother embodiments, a composition comprises a co-solvent at about 2%,about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%,about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%,about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%,about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%,about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%,about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%,about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%,about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about94%, about 95%, about 96%, about 97%, about 98%, or about 99%.

Examples of co-solvents include, but are not limited to, alcohols,silicones, polyethylene glycol, propylene glycol, glycerin, petrolatum,hydroxymethylcellulose, methylcellulose, and combinations thereof. In anembodiment, a co-solvent is polyethylene glycol.

In an embodiment, a composition comprises DMSO in the range of about0.01% to 99.99% and further comprises at least one penetrant in therange of 0.01% to about 99.99%. In an embodiment, a compositioncomprises DMSO and further comprises at least one penetrant in the rangeof about 0.1% to about 50%. In another embodiment, a compositioncomprises DMSO and further comprises at least one penetrant in the rangebetween about 5% and about 50%. In another embodiment, a compositioncomprises DMSO and further comprises at least one penetrant in the rangebetween about 10% and about 99%. In an embodiment, a compositioncomprises DMSO, at least one co-solvent, and at least one penetrant. Inan embodiment, a co-solvent is also a penetrant.

In an embodiment, where possible, compositions may includepharmaceutically acceptable salts of compounds in the composition. In anembodiment, compositions comprise acid addition salts of the presentcompounds. In an embodiment, compositions comprise base addition saltsof the present compounds. As used herein, the term pharmaceuticallyacceptable salts or complexes refers to salts or complexes (e.g.,solvates, polymorphs) that retain the desired biological activity of theparent compound and exhibit minimal, if any, undesired toxicologicaleffects.

In various embodiments, the compositions encompassed herein comprisepharmaceutically acceptable excipients such as those listed inREMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 866-885 (Alfonso R.Gennaro ed. 19th ed. 1995; Ghosh, T. K.; et al. TRANSDERMAL AND TOPICALDRUG DELIVERY SYSTEMS (1997), hereby incorporated herein by reference,including, but not limited to, protectives, adsorbents, demulcents,emollients, preservatives, antioxidants, moisturizers, buffering agents,solubilizing agents, skin-penetration agents, and surfactants.

Protectives and adsorbents include, but are not limited to, dustingpowders, zinc sterate, collodion, dimethicone, silicones, zinccarbonate, aloe vera gel and other aloe products, vitamin E oil,allantoin, glycerin, petrolatum, and zinc oxide.

Demulcents include, but are not limited to, benzoin, hydroxypropylcellulose, hydroxypropyl methylcellulose, and polyvinyl alcohol.

Emollients include, but are not limited to, animal and vegetable fatsand oils, myristyl alcohol, alum, and aluminum acetate.

Preservatives include, but are not limited to, chlorine dioxide,quaternary ammonium compounds, such as benzalkonium chloride,benzethonium chloride, cetrimide, dequalinium chloride, andcetylpyridinium chloride; mercurial agents, such as phenylmercuricnitrate, phenylmercuric acetate, and thimerosal; alcoholic agents, forexample, chlorobutanol, phenylethyl alcohol, and benzyl alcohol;antibacterial esters, for example, esters of parahydroxybenzoic acid;and other anti-microbial agents such as chlorhexidine, chlorocresol,benzoic acid and polymyxin.

Suitable antioxidants include, but are not limited to, ascorbic acid andits esters, sodium bisulfate, butylated hydroxytoluene, butylatedhydroxyanisole, tocopherols, and chelating agents like EDTA and citricacid.

Suitable moisturizers include, but are not limited to, glycerin,sorbitol, polyethylene glycols, urea, and propylene glycol.

Suitable solubilizing agents include, but are not limited to, quaternaryammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, andpolysorbates.

Suitable skin-penetration agents include, but are not limited to, ethylalcohol, isopropyl alcohol, octylphenylpolyethylene glycol, oleic acid,polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fattyacid esters (e.g., isopropyl myristate, methyl laurate, glycerolmonooleate, and propylene glycol monooleate); and N-methylpyrrolidone.

In an embodiment, a composition comprises PVP-I, DMSO, and polyethyleneglycol and a gelling agent. In an embodiment, a composition comprises0.25% PVP-I, 44% DMSO, 10% polyethylene glycol and 3% gelling agent. Inan embodiment, the composition is substantially anhydrous. In anembodiment, a composition comprises PVP-I, DMSO, hydroxyethylcellulose,propylene glycol and glycerin. In an embodiment, a composition comprises2% PVP-I, about 40% DMSO, and 10-33% propylene glycol and at least oneadditional inactive ingredient.

In one embodiment, the composition includes 0.15-0.5% PVP-I, 40-49%DMSO, 8-15% alcohol, 18-25% polyethylene glycol, 2.5-5.0% gellingagents, and 0-3% water. In one embodiment, the composition includesaprotic solvents. In one embodiment, the composition includes 0.15-0.5%PVP-I, 40-45% DMSO, 10-35% polyethylene glycol, 2.5-3.5% gelling agents,and 0-3% water. In one embodiment, the composition includes aproticsolvents.

In one embodiment, the invention comprises DMSO 40-50% (w/w),0.25%-0.55% PVP-I (w/w) and hydroxypropyl methylcellulose orhydroxymethyl cellulose or hydroxyethyl cellulose.

In one embodiment, the composition is a solution and can be formulatedas a semi-solid, e.g., a gel, ointment or cream; tincture; foam; aerosolor another common pharmaceutical dosage form. In one embodiment, thecomposition is a 0.25% PVP-I/44% DMSO solution dissolved in 3% gel, suchas hydroxyethyl cellulose.

Stability

A. Visible Loss of Chromophore

Topical ophthalmic compositions comprising variations of the amounts andcombinations of povidone-iodine, DMSO, and gelling agent ingredientswere prepared to demonstrate the unpredictability of the stability forthe subject compositions.

Compositions that are highly unstable, and are thus not suitable oruseful as a topical ophthalmic preparation, will lose color and appearcolorless within about 72 hours of making the preparation. The colorlessstate is a result of loss of titratable iodine compared with the amountof iodine in the povidone-iodine starting material. No furtherconfirmatory testing of titratable iodine is needed for compositionsthat are colorless within 72 hours of preparation.

Compositions were prepared with 0.15%, 0.25%, and 0.5% povidone-iodine.For these compositions, DMSO was provided in amounts of 0% or in anamount of 30% to 90%. Specific compositions comprising DMSO wereprepared comprising 44% DMSO. Gelling agent was provided in amounts of0%, 0.5%. 1.0%, 1.5%, 2.5% or 3.0%.

All of the prepared compositions comprising aqueous PVP-I only andwater, and 0% DMSO and 0% gelling agent were colorless within 72 hoursand were not stable.

For preparations comprising 0.15% povidone-iodine and DMSO within therange of 30% to 90%, the compositions retained color and were stablewhen the gelling agent was provided at 3%. Long-term stability of thecompositions which retained color for 72 hours or longer was confirmedby USP assay for titratable iodine compared to povidone-iodine startingmaterial. The stable compositions of the subject invention retained atleast 85% of titratable iodine in the povidone-iodine starting materialfor up to 18 months.

For preparations comprising 0.25% povidone-iodine and DMSO within therange of 30% to 90%, the compositions retained color and were stablewhen the amount of gelling agent was greater than or equal to 2.5%.Long-term stability of the compositions which retained color for 72hours or longer was confirmed by USP assay for titratable iodinecompared to povidone-iodine starting material. The stable compositionsof the subject invention retained at least 85% of titratable iodine inthe povidone-iodine starting material for up to 18 months.

For preparations comprising 0.5% povidone-iodine and DMSO within therange of 30% to 90%, the compositions retained color and were stablewhen the amount of gelling agent was greater than or equal to 2.5%.Long-term stability of the compositions which retained color for 72hours or longer was confirmed by USP assay for titratable iodinecompared to povidone-iodine starting material. The stable compositionsof the subject invention retained at least 85% of titratable iodine inthe povidone-iodine starting material for up to 18 months.

These experimental results demonstrate that stability of the specificcombination of ingredients, and within specific range amounts, namely,0.15% to 0.5% povidone-iodine; 30% to 90% DMSO, and 2.5% to 5% gellingagent, are stable whereas compositions which deviate from these specificingredients in specific range amounts are unstable. A preferred gellingagent is a cellulosic polymer, such as hydroxyethyl cellulose (HEC),hydroxymethyl cellulose (HMC), hydroxypropyl methylcellulose (HPMC), andthe like. A most preferred gelling agent is hydroxyethyl cellulose(HEC).

A table showing results of the above-described experiments usingselected compositions is provided in Table 1, below:

TABLE 1 Aqueous Research Formulations with Varying Amounts of PVP-I,DMSO, and Gelling Agent Formulation PVP-I DMSO HEC Gel Initial ID #(w/w) (w/w) (w/w) Color 72 hrs. 3 mos. 6 mos. 12 mos. 18 mos. #A44300.25  44%   3% Faint Faint Faint Faint Faint Faint Yellow Yellow-Yellow- Yellow- Yellow- Yellow- unchanged; unchanged; unchanged;unchanged; unchanged; Titratable Titratable Titratable TitratableTitratable iodine, via iodine, via iodine, via iodine, via iodine, viaUSP USP USP USP USP method- method- method- method-method- >85% >85% >85% >85% >85% #A0000 0.25 0.0% 0.0% Faint colorlessNA NA NA NA yellow #A4400 0.25  44% 0.0% Faint colorless NA NA NA NAyellow #A4405 0.25  44% 0.5% Faint colorless NA NA NA NA yellow #A00050.25 0.0% 0.5% Faint colorless NA NA NA NA yellow #A4410 0.25  44% 1.0%Faint colorless NA NA NA NA yellow #A0015 0.25 0.0% 1.5% Faint colorlessNA NA NA NA yellow #B4430 0.5  44% 3.0% Medium Med Med Med Med Medyellow Yellow- Yellow- Yellow- Yellow- Yellow- unchanged; unchanged;unchanged; unchanged; unchanged; Titratable Titratable TitratableTitratable Titratable iodine, via iodine, via iodine, via iodine, viaiodine, via USP USP USP USP USP method- method- method- method-method- >85% >85% >85% >85% >85% #B0000 0.5 0.0% 0.0% Medium colorlessNA NA NA NA Yellow #B4400 0.5  44% 0.0% Medium colorless NA NA NA NAyellow #B0005 0.5 0.0% 0.5% Medium colorless NA NA NA NA yellow #B00200.5 0.0% 1.5% Medium colorless NA NA NA NA yellow #C4430 0.15  44% 3.0%Faint Faint Faint Faint Faint Faint yellow yellow- yellow- yellow-yellow- yellow- unchanged; unchanged; unchanged; unchanged; unchanged;Titratable Titratable Titratable Titratable Titratable iodine, viaiodine, via iodine, via iodine, via iodine, via USP USP USP USP USPmethod- method- method- method- method- >85% >85% >85% >85% >85% #C00000.15 0.0% 0.0% Faint colorless NA NA NA NA yellow #C4400 0.15  44% 0.0%Faint colorless NA NA NA NA yellow #C4405 0.15  44% 0.5% Faint colorlessNA NA NA NA yellow #C4410 0.15  44% 1.5% Faint colorless NA NA NA NAyelow

In one embodiment, the formulations are stable at room temperature 25°C. for at least 6 months, 12 months, 18 months and 24 months. Stabilityis defined as where the final PVP-I concentration is at least 85%-120%,according to the USP titration method for povidone-iodine, of thelabeled concentration.

In one embodiment, the formulations are stable at temperature 2-8° C.for at least 6 months, 12 months, 18 months and 24 months. Stability isdefined as where the final PVP-I concentration is at least 85%-120%,according to the USP method of the labeled concentration (e.g. if thelabel is 2% PVP-I providing for 0.2% iodine, therefore 90% would be 0.18elemental iodine).

In one embodiment, the formulations are stable at room temperature −10to −25° C. for at least 6 months, 12 months, 18 months and 24 months.Stability is defined as where the final PVP-I concentration is at least85%-120%, according to the USP method of the labeled concentration (e.g.if the label is 2% PVP-I providing for 0.2% iodine, therefore 90% wouldbe 0.18 elemental iodine).

In one embodiment, the formulations are stable at room temperature15-30° C. for at least 6 months, 12 months, 18 months and 24 months.Stability is defined as where the final PVP-I concentration is at least85%-120%, according to the USP method, of the labeled concentration(e.g. if the label is 2% PVP-I providing for 0.2% iodine, therefore 90%would be 0.18 elemental iodine).

In one embodiment, the formulations are stable at room temperature 40°C. for at least 1 months, 3 months, 6 months, 12 months, 18 months and24 months. Stability is defined as where the final PVP-I concentrationis at least 85%-120%, according to the USP method of the labeledconcentration (e.g. if the label is 2% PVP-I providing for 0.2% iodine,therefore 90% would be 0.18 elemental iodine).

Methods of Preparation and Use

It is known to one of skill in the art that PVP-I aqueous solutions aredifficult to stabilize at low PVP-I concentrations over a long period oftime. By way of a non-limiting example, at concentrations of PVP-I lessthan about 0.6% (w/w, aqueous), PVP-I aqueous solutions rapidly decay toyield complex mixtures of iodinated and iodine-free constituents.

As described herein, it was surprisingly found that in the aprotic DMSOsolvent system encompassed by the disclosure set forth herein, PVP-I gelsolutions as low as 0.15% can be easily prepared and maintained asstable compositions for long periods of time. Also as described herein,hydrated DMSO solutions prepared from aqueous PVP-I and sufficient(about 3% or greater) gelling agent, demonstrate increased stability forthe PVP-I component over at least 12 months at room temperature.

In an embodiment, a composition comprises dry, solid or powdered PVP-Idissolved or suspended in a composition comprising or consisting ofDMSO. In another embodiment, DMSO is added to an aqueous preparationcomprising or consisting of PVP-I.

Based on the disclosure herein, one of ordinary skill in the art willunderstand how to prepare a composition to arrive at the desired amountsof iodine, iodophor, and DMSO, among other possible components of thecomposition encompassed herein, without undue experimentation.

By way of a non-limiting example, a therapeutically-effectivepharmaceutical composition is prepared using solid PVP-I, which isdissolved or suspended in DMSO. In an aspect, the composition isanhydrous. In an aspect, the composition is substantially anhydrous. Inanother embodiment, DMSO can be added to aqueous solutions of PVP-I toprepare a therapeutically-effective pharmaceutical composition. In anembodiment, DMSO is used in the range of 30%-99% as a co-solvent withwater and other non-aqueous co-solvents. In an embodiment, a formulationincludes one or more excipients. By way of a non-limiting example,excipients include, but are not limited to, sodium chloride, sodiumdihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrousand water, as well as others known to those skilled in the art.

In an embodiment, a composition is prepared by adding PVP-I (w/v,aqueous) to pure DMSO q.s. to yield a resulting solution of 0.15-1.5%PVP-I (w/w) with DMSO. In another embodiment, compositions are preparedby dissolving solid PVP-I in pure DMSO q.s to obtain any of 0.1%, 0.2%,0.25%, 0.3%, 0.35%, 0.4%, 0.45%, or 0.5% PVP-I (w/w) compositions, withDMSO as the solvent. In yet another embodiment, compositions areprepared by dissolving solid PVP-I in pure DMSO q.s to obtain anycomposition set forth, described, and/or encompassed herein. Similarcompositions comprising aqueous PVP-I (with and without excipientscommonly used and/or known in the art) and DMSO can be prepared from astock 10% PVP-I aqueous solution and pure DMSO. Gelling agent can beadded at an amount up to 5% (w/w) of the final concentration of thecomposition, preferably between about 2.0% and 5.0%, more preferablybetween about 2.5% and 5.0%, and most preferably about 3%.

It will be understood by the skilled artisan, however, that any startingcomposition of PVP-I, solid or liquid, may be used when the appropriatedilutions and adjustments are made to result in the desired final PVP-Iconcentration. Similarly, any starting composition of iodophor orelemental iodine may be used when the appropriate dilutions andadjustments are made to result in the desired final iodophor orelemental iodine concentration, respectively.

It will be understood, based on the disclosure set forth herein, in viewof the skill in the art, that specific dosage for compounds andcompositions encompassed herein may be determined empirically throughclinical and/or pharmacokinetic experimentation, and that such dosagesmay be adjusted according to pre-specified effectiveness and/or toxicitycriteria. It will also be understood that a specific dosage andtreatment regimen for any particular patient will depend upon a varietyof factors, including the activity of the specific compounds employed,the characteristics of the patient, drug combination, the judgment ofthe treating physician and the nature and severity of the particulardisease or condition being treated.

In an embodiment, a therapeutic composition is prepared by optimizingone or more compounds for use in a dosage form different than that whichis typically used for the compound. In an embodiment, a compound that isnot typically administered in a topical dosage form is developed for usein a topical dosage form. The chemical and biological assays requiredfor such development are known to one of skill in the art. Thedisclosure herein provides the skilled artisan with the guidance as tohow to prepare such compounds and compositions comprising suchcompounds.

In an embodiment, a method of treating a subject having an ocularsurface disease complicated by microbial colonization and/or infectionincludes administration of a composition set forth, described, and/orencompassed herein to treat the ocular surface disease, and thetreatment of the ocular surface disease includes at least one ofpreventing or slowing the progression of the infection, preventing thespread of the infection, eradicating at least some of the infection, anderadicating the entire infection.

In an embodiment, a therapeutic composition is administered on aschedule once a day. In an embodiment, a therapeutic composition isadministered twice a day. Typically, a gel composition of the subjectinvention can be administered as a ribbon having a length of about 1 cmto about 5 cm, up to 1 cm in diameter, onto the eye, under the eyelid,or at the periocular region of the eye to be treated.

In an embodiment, a therapeutic composition is administered three timesa day, four times a day, five times a day, or more. In an embodiment, atherapeutic composition is administered less frequently than once a day.In an embodiment, a therapeutic composition is administered once everytwo days, once every three days, once every four days, once every fivedays, once every six days, or once every seven days. In an embodiment, atherapeutic composition is administered less frequently than once aweek. In an embodiment, a therapeutic composition is administered once amonth. In an embodiment, a therapeutic composition is administered twicea month.

In an embodiment, a therapeutic dosing regimen is continued for at leastone day, at least two days, at least three days, at least four days, atleast five days, at least six days, or at least seven days. In anembodiment, a therapeutic dosing regimen is continued for at least oneweek, at least two weeks, at least three weeks, at least four weeks, atleast six weeks, at least eight weeks, at least ten weeks, at leasttwelve weeks, at least fourteen weeks, or at least sixteen weeks. In anembodiment, a therapeutic dosing regimen is continued for at least onemonth, at least two months, at least three months, at least four months,at least five months, at least six months, at least nine months, or atleast twelve months.

The invention is further described by the following examples. In anaspect, the following examples demonstrate effective and/or successfultreatment of the identified conditions using compositions and methodsencompassed by the present disclosure. It should be recognized thatvariations based on the inventive features are within the skill of theordinary artisan, and that the scope of the invention should not belimited by the examples. To properly determine the scope of theinvention, an interested party should consider the claims herein, andany equivalent thereof. The entire disclosure of international patentapplications, PCT/US2012/036942 and PCT/US2012/065298 are herebyincorporated herein by reference as if fully set forth herein. Inaddition, all citations herein are incorporated by reference, and unlessotherwise expressly stated, all percentages are by weight/weight.

Additional examples of useful compositions described in this inventioninclude the formulation of creams, petrolatum balms, salves, sprays, andother formulations well known to those in the art suitable for topicaladministration to the ocular surface or are “ophthalmically acceptable”compositions.

While the foregoing written description enables a person ordinarilyskilled in the art to reproduce and use what is considered presently tobe the best mode thereof, those of ordinary skill will understand andappreciate the existence of variations, combinations, derivatives,analogs and equivalents of the specific embodiments, methods andexamples provided above. The invention should therefore not be limitedby the above described embodiments, examples and methods by instead byall embodiments, examples and methods within the scope and spirit of thepresent invention.

Clinical Trial Results and Clinical Efficacy

In a 12-week clinical trial for treating blepharitis, the endpoint ofcomplete eradication and/or the endpoint of substantial reduction in thesigns and symptoms of blepharitis. The results from a randomized,controlled clinical trial demonstrates the effectiveness a formulationof the subject invention comprising up to 1-2% povidone-iodine, with apenetration enhancer, DMSO, which can successfully eliminateblepharitis. The blepharitis infections are assessed at 2-weekintervals, with complete resolution demonstrated by the 12-week clinicalassessment. By the end of a 12-week study complete resolution of signsand symptoms of blepharitis in at least 10%, at least 15%, at least 20%,at least 30% or at least 40% of study subjects is observed by the12-week end-of-study visit.

In addition, a recent study of 18 patients showed that a gel formulationcomprising 0.25% or 0.5% PVP-I gel formulation exhibits less irritationwhen administered to the Lower Lid Conjunctival Fornix. These resultsare summarized in Table 2, below:

TABLE 2 Ocular Irritation Study Using 0.25% PVP-I/DMSO (Dose “A”) Gel or0.5% PVP-I/DMSO (Dose “B”) Gel In OD Lower Lid Conjunctival Fornix¹Patient Dose Injection Number Applied Discharge (redness) Burning Itch001 A 0 0 0 0 002 A 0 0 0 0 003 A 0 0 0 0 004 A 0 0 0 0 005 A 1 0 0 0006 A 1 0 0 0 007 A 0 0 0 0 008 A 1 0 0 0 009 A 0 0 0 0 010 A 0 0 0 0011 A 0 1 1 0 012 A 0 0 1 0 013 B 0 0 0 0 014 B 0 0 0 0 015 B 1 0 0 0016 B 1 0 1 0 017 B 1 1 1 0 018 B 0 1 1 0 ¹All applications are ½″ribbon applied directly into lower lid conjunctival fornix; all gradingfor all signs and symptoms is 0-3 on a 4-point scale where 0 = absent, 1= mild, 2 = moderate and 3 = severe.

In the examples from the clinical trials above, a liquid formulation wasexpected to provide adequate efficacy against warts and blepharitis.Most wart treatments are liquids. Surprisingly, it was found that a gelformulation provides unexpected advantages and increased efficacycompared with similar concentrations of PVP-I in a liquid formulation.

EXAMPLES Example 1 Anterior Blepharitis; Treated with 1.0% PVP-I in 30%USP Grade DMSO with Polypropylene Glyclol and Hydroxymethylcellulose

This patient was suffering from anterior blepharitis. In this commontype of blepharitis, the anterior lid margin demonstrates madarosis,collarettes, scurf, lash debris and bacterial overgrowth. The lid marginmay also be erythematous along with the conjunctiva and a decreased tearbreak up time is present. In this patient the condition had persistedfor over 7 years and taken a chronic course. The patient had triednumerous antibiotics, steroids, lid scrubs, omega 3 fatty acids, andanti-inflammatories without benefit. Prepared was a composition asdisclosed herein using 1.0% PVP-I in 30% DMSO with polypropylene glycoland hydroxymethylcellulose. The patient was treated by applying thesolution topically to the eyelid and conjunctiva twice daily. Within oneweek, improvement was noted in and around the eyelid. After two weeksthe condition rapidly improved, as the conjunctival erythema abated,tear break up time and dry eye symptoms normalized. Close inspection ofthe anterior lid eyelid margin revealed healthy cilia without associateddebris or bacterial overgrowth.

Example 2 Posterior Blepharitis; Treated with 0.2% PVP-I in 35%% USPGrade DMSO with Hydroxyethyl Cellulose

This patient was suffering from posterior blepharitis. In this mostcommon type of blepharitis, the posterior lid margin demonstratesmeibomian gland thickening, keratinization, fat saponification, anddilated, telangectatic lid vessels. The lid margin may also beerythematous along with the conjunctiva and decreased tear break up timeis evident. In this patient the condition had persisted for over 7 yearsand taken a chronic course. The patient had tried numerous antibiotics,steroids, lid scrubs, omega 3 fatty acids and anti-inflammatorieswithout benefit. Prepared was a composition as disclosed herein using0.2% PVP-I in 35%% DMSO with hydroxyethyl cellulose. The patient wastreated by applying the solution topically to the eyelid and conjunctivatwice daily. Within one week, improvement was noted in and around theeyelid. After two weeks the condition rapidly improved, as theconjunctival erythema abated, tear break up time and dry eye symptomsnormalized. Close inspection of the posterior lid eyelid margin revealedhealthy meibomian secretions, attenuation of posterior lid blood vesselsand lack of erythema.

Example 3 A. Rosacea Blepharitis; Treated with 0.5% PVP-I in 38% USPGrade DMSO with Hydroxyethyl Cellulose

This patient was suffering from Rosacea blepharitis. In this type ofblepharitis, the posterior lid margin demonstrates meibomian glandthickening, keratinization, fat saponification, and dilated,telangectatic lid vessels. Anterior lid margin may also demonstratescurf and bacterial overgrowth. The lid margin may also be erythematousalong with the conjunctiva and a decreased tear break up time ispresent. In this patient the condition had persisted for over 7 yearsand taken a chronic course. The patient had tried numerous antibiotics,steroids, lid scrubs, omega 3 fatty acids and anti-inflammatorieswithout benefit.

Prepared was a composition as disclosed herein using 0.5% PVP-I in 38%DMSO with hydroxyethyl cellulose. The patient was treated by applyingthe solution topically to the eyelid and conjunctiva twice daily. Withinone week improvement was noted in and around the eyelid. After two weeksthe condition rapidly improved, as the conjunctival erythema abated,tear break up time and dry eye symptoms normalized. The dilated,tortuous posterior lid margin vessels had significantly attenuated andmeibomian secretions were healthy. Close inspection of the anterior lideyelid margin revealed healthy cilia without associated debris orbacterial overgrowth.

B. Rosacea Blepahritis; Treated with 1% PVP-I in 44% USP Grade DMSO with4% Hydroxyethylcellulose in Water

A 78-year-old male with a past ocular history of glaucoma andpseudophakia presented with long standing ocular dryness, grittiness,periocular erythema and eyelid crusting. On facial inspection, nasal andfacial telangiectasia with flushing were evident. His topical medicalregimen included Latanoprost 1 drop QHS OU, Brimonidine 1 drop BID OU,and Dorzolamide/Timolol 1 drop BID OU. The patient endorsed utilizationof a variety of medicines and treatments to abate this condition,however, they were of little benefit. Failed therapies included topicalsteroids, antibiotics including azithromycin, combination medicines, andcyclosporine. Oral medicines including doxycycline and DHA/ALA/EPA werealso ineffective.

Slit lamp biomicroscopic examination revealed bilateral anterior lidmargin erythema, crusting and thickening. Lash examination revealed somebreakage with scurf-like deposition. Inspection of the posterior eyelidsrevealed inspissated meibomian glands with capping and turbidsecretions. Further towards the posterior tarsal area, dilated, engorgedtelangiectatic vessels were present. The marginal lid erythema extendednot only to the tarsal plate, but also to the inferior bulbarconjunctiva. Tear break-up time was notably decreased and corneaerevealed inferior, bilateral punctate epithelial erosions. A diagnosisof rosacea blepharoconjunctivitis was made.

The patient was given a topical gel of 1% PVP-I in a dimethylsulfoxide(DMSO) vehicle that was prepared from a licensed compounding pharmacy.The treatment was administered twice daily and delivered by rubbing thegel onto the lash line and eyelid. At the first follow up visit one weeklater, remarkable improvements were noted. Most prominently, much of theconjunctivitis, anterior lid erythema and thickening had reversed. Thepatient was instructed to decrease the gel to once daily, but continuetreatment for a total of one month. At this second follow up visit, notonly were the initial improvements conserved, but the posterior lidmargin vessels and telangiectasia had begun to attenuate and involute.Moreover, meibomian capping was no longer present and secretions wereless viscous. Besides occasional mild tingling at the application site,the patient reported no other adverse effects

Example 4 Demodex Blepharitis; Treated with 1.0% PVP-I in 40% USP GradeDMSO with Petrolatum

This patient was suffering from anterior Demodex blepharitis. In thistype of blepharitis, the anterior lid margin demonstrates madarosis,collarettes in cylindrical pattern and lash debris. Decreased tear breakup time is also evident. The posterior lid margin may also beerythematous and demonstrate meibomian inspissation, fat saponification,and bacterial overgrowth. In this patient the condition had persistedfor over 7 years and taken a chronic course. The patient had triednumerous antibiotics, steroids, tea tree oils, lid scrubs omega 3 fattyacids and anti-inflammatories without benefit. Cilia were epilated andexamined under the microscope positively identifying Demodexfolliculorum. Prepared was a composition as disclosed herein using 1.0%PVP-I in 40% DMSO with petrolatum. The patient was treated by applyingthe solution topically to the eyelid and conjunctiva twice daily. Withinone week, improvement was noted in and around the eyelid. After twoweeks the condition rapidly improved, as the conjunctival erythemaabated, tear break up time and dry eye symptoms were normalized.Posterior lid margin demonstrated normal meibomian secretions.Microscopic assessment of cilia was negative for Demodex mites.

Example 5 Blepharoconjunctivitis; Treated with 0.3% PVP-I in 33% USPGrade DMSO with Glycerin

This patient was suffering from blepharoconjunctivits. In this type ofocular inflammation, the anterior lid margin demonstrates madarosis,collarettes, scurf, lash debris and bacterial overgrowth. The posteriorlid margin may also be erythematous, and demonstrate meibomianinspissation, capping, and keratinization. A hallmark of this process isabundant conjunctival injection which is secondary to anterior andposterior lid inflammation. In this patient the condition had persistedfor over 1 week with an acute course. The patient had tried numerousantibiotics, steroids, lid scrubs, omega 3 fatty acids, andanti-inflammatories without benefit. Prepared was a composition asdisclosed herein using 0.3% PVP-I in 33% DMSO with glycerin. The patientwas treated by applying the solution topically to the eyelid andconjunctiva twice daily. Within one week, improvement was noted in andaround the eyelid. After two weeks the condition rapidly improved, astear break up time and dry eye symptoms normalized. Close inspection ofthe anterior lid eyelid margin revealed healthy cilia without associateddebris or bacterial overgrowth. Posterior lid margin inspection revealedhealthy meibomian secretions and decreased lid erythema. Theconjunctival examination revealed quiet and healthy tissue withoutinflammation.

Example 6 Adenoviral Conjunctivitis; Treated with 0.5% PVP-I in 44% USPGrade DMSO with 3% Hydroxyethylcellulose

This patient was suffering from adenoviral conjunctivitis. This commontype of conjunctivitis follows a recent viral upper repiratory infectionor contact with another infected person. Pre-auricular adenopathy isoften present. In this patient, the conjunctiva demonstrated diffuseinjection with chemosis. There was frequent clear ocular dischargepresent. Eyelid eversion revealed 3+ follicular reaction with fewscattered petechiae. RPS Adenodetector sampling identified the causativeagent to be an Adenovirus serotype. The patient had tried numerousantibiotics, steroids, lid scrubs and anti-inflammatories withoutbenefit. Prepared was a composition as disclosed herein using 0.5% PVP-Iin 44% DMSO with hydroxyethylellulose 3%. The patient was treated byapplying the gel topically to the eyelid and conjunctiva three timesdaily. Within one week, improvement was noted in and around the eyelidevidenced by decreased chemosis and lid edema. At two weeks thecondition was resolved, as the conjunctival erythema, discharge andfollicles were no longer present. There was no development of cornealinfiltrates or pseudomembranes.

Example 7 Epidemic Adenoviral Conjunctivitis; Treated with 0.5% PVP-I in41.5%% USP Grade DMSO with 3% Hydroxyethyl Cellulose

This patient was suffering from epidemic adenoviral conjunctivitis. Thistype of conjunctivitis follows a recent viral upper repiratory infectionor contact with another infected person. Pre-auricular adenopathy isoften present. In this patient, the conjunctiva demonstrated diffuseinjection with chemosis along with pseudomembrane formation. There wasfrequent clear ocular discharge present. Eyelid eversion revealed 3+follicular reaction with few scattered petechiae. Corneal examinationshowed multifocal, sub-epithelial infiltrates. RPS Adenodetectorsampling identified the causative agent to be an Adenovirus serotype.The patient had tried numerous antibiotics, steroids, lid scrubs andanti-inflammatories without benefit. Prepared was a composition asdisclosed herein using 0.5% PVP-I in 41.5% DMSO with 3% hydroxyethylcellulose. The patient was treated by applying the gel topically to theeyelid and conjunctiva three times daily. Within one week, improvementwas noted in and around the eyelid. At two weeks the condition wasresolved, as the conjunctival erythema, discharge, follicles andpseudomembranes were no longer present. The corneal infiltrates had alsoresolved and the cornea was clear and compact.

Example 8 Bacterial Conjunctivitis; Treated with 0.25% PVP-I in 44% USPGrade DMSO with Hydroxyethylcellulose 3%

This patient was suffering from bacterial conjunctivitis. In this typeof conjunctivitis there is often bacterial overgrowth and infiltrationof the conjunctival epithelial layers. In this patient, conjunctiva alsodemonstrated diffuse injection with chemosis along with inflammatorymembrane formation. There was frequent purulent ocular dischargepresent. Eyelid eversion revealed 3+ inflamed palpebral conjunctiva withfew petechiae. Conjuctival cultures identified the causative agent asStaphylococcus Aureus. The patient had tried numerous antibiotics,steroids, lid scrubs and anti-inflammatories without benefit. Preparedwas a composition as disclosed herein using 0.25% PVP-I in 44% DMSO withhydroxyethylcellulose 3%. The patient was treated by applying the geltopically to the eyelid and conjunctiva three times daily. Within threedays, improvement was noted in and around the eyelid. At one week thecondition was resolved, as the conjunctival erythema, discharge,follicles and inflammatory membranes were no longer present.

Example 9 Herpes Simplex Virus Epithelial Keratitis; Treated with 1.0%PVP-I in 49% USP Grade DMSO with 2.5% Hydroxyethylcellulose

This patient was suffering from herpes simplex virus epithelialkeratitis. In this type of keratitis there is often active replicatingvirus present within epithelial dendrites. With immune system weakening,the virus reactivates in the sensory ganglia and descends to infect thecornea. It can often manifest as recurrent disease. In this patient, theconjunctiva demonstrated diffuse injection and the cornea showedstaining epithelial ulcerations in serpentine or dentritic form withterminal bulbs. Millipore testing reveals herpes simplex virus as thecausative agent. The patient had tried numerous antibiotics, steroids,oral and topical anti-virals and anti-inflammatories without benefit.Prepared was a composition as disclosed herein using 1.0% PVP-I in 49%DMSO with 2.5% hydroxyethylcellulose. The patient was treated byapplying the solution topically to the eye three times daily. Withinthree days, improvement was noted in and around the eye. The dendritesbegan to re-epithelialize and active virus replication was halted. Atone week the condition was resolved and there was no evidence of theprevious corneal lesions. The conjunctiva was white and quiet.

Example 10 Herpes Simplex Virus Stromal Keratitis; Treated with Aqueous0.15% PVP-I in 35% USP Grade DMSO with 3% Hydroxyethyl Cellulose

This patient was suffering from herpes simplex virus stromal keratitis.In this type of keratitis there is often immune activation of the hostsecondary to molecular mimicry causing stromal corneal swelling. Theremay or may not be active replicating virus. It can often manifest asrecurrent disease. In this patient, the conjunctiva demonstrated diffuseinjection and the cornea showed diffuse corneal swelling withopacification. The patient had tried numerous antibiotics, steroids,oral and topical anti-virals and anti-inflammatories without benefit.Prepared was a composition as disclosed herein using 0.15% PVP-I in 35%DMSO with hydroxyethyl cellulose 3%. The patient was treated by applyingthe solution gel to the eye three times daily. Within three days,improvement was noted in and around the eye. The stromal edema began toclear and the patient was without any staining dendrites. At one weekthe condition was resolved and there was no evidence of the previouscorneal lesions, cicatrization, or neovascularization. The conjunctivawas white and quiet.

Example 11 Herpes Simplex Virus Endothelial Keratitis; Treated withAqueous 0.5% PVP-I in 48% USP Grade DMSO with 3% Hydroxyethyl Cellulose

This patient was suffering from herpes simplex virus endothelialkeratitis. In this type of keratitis there is often immune activation ofthe host secondary to molecular mimicry directed at endothelial cells.There may or may not be active replicating virus. It can often manifestas recurrent disease. In this patient, the conjunctiva demonstrateddiffuse injection and the cornea showed disciform endothelialinflammation with keratic precipitates. Some stromal corneal edema wasalso present. The anterior chamber revealed rare inflammatory cells andmild trabeculitis. The patient had tried numerous antibiotics, steroids,oral and topical anti-virals and anti-inflammatories without benefit.Prepared was a composition as disclosed herein using 0.5% PVP-I in 48%DMSO with 3% hydroxyethyl cellulose. The patient was treated by applyingthe gel topically to the eye three times daily. Within three days,improvement was noted in and around the eye. The stromal edema began toclear and the keratic precipitates attenuated. The anterior chamber celland flare was no longer present. At one week the condition was resolvedand there was no evidence of the previous corneal swelling. There was noresidual corneal cicatrization, or neovascularization. The conjunctivawas white and quiet.

Example 12 Hepres Zoster Ophthalmicus; Treated with Aqueous 1.8% PVP-Iin 40% USP Grade DMSO with Petralatum

This patient was suffering from herpes zoster virus epithelialkeratitis. In this type of keratitis there is often viral infectionwithin the eye along with erythematous macules and excoriations indermatomal distribution. With immune system weakening, the herpes zostervirus is reactivated within the ophthalmic division of the trigeminalnerve. In this patient, the conjunctiva demonstrated diffuse injectionand the cornea showed rose bengal staining epithelial “stuck on”dendrites in without terminal bulbs. The underlying corneal stromademonstrated central edema without keratic precipitates. Fundusexamination was negative for vasculitis. The patient had tried numerousantibiotics, steroids, oral and topical anti-virals andanti-inflammatories without benefit. Prepared was a composition asdisclosed herein using 1.8% PVP-I in 40% DMSO with petralatum. Thepatient was treated by applying the solution topically to the eye threetimes daily. Within three days, improvement was noted in and around theeye. The dendrites began to re-epithelialize and active virusreplication was halted. At one week the condition was resolved and therewas no evidence of the previous corneal lesions. The conjunctiva waswhite and quiet and the cornea was clear and compact.

Example 13 Gram Positive Bacterial Corneal Ulceration; Treated withAqueous 0.35% PVP-I in 45% USP Grade DMSO with 3% Hydroxyethylcellulose

This patient was suffering from a bacterial corneal ulceration. In thistype of infection there is often a history of contact lens use, however,this is not a prerequisite. Bacteria is introduced into the eye througha small break in the epithelium and gains foothold to the underlyingstructures. In this patient, the conjunctiva demonstrated diffuseinjection with pyogenic discharge. The cornea demonstrated a central,three-millimeter circular infiltrate with overlying central epithelialdefect. The infiltrate induced stromalysis and the resultant cornea hadthinned by approximately thirty percent. There was a one millimeterlayered hypopyon in the anterior chamber. Corneal cultures were taken,and Coagulase-negative Streptococcal species were identified. Thepatient had tried numerous antibiotics, steroids, oral and topicalanti-virals and anti-inflammatories without benefit. Prepared was acomposition as disclosed herein using aqueous 0.35% PVP-I in 45% DMSOwith 3% hydroxyethylcellulose. The patient was treated by applying thesolution topically to the eye six times daily. Within three days,improvement was noted in and around the eye. The corneal melt had haltedand re-epithelialization had taken place. At one week the hypopyon hadresolved, the conjunctiva cleared and a small central infiltrateremained. By week two, the patient was healed and no active bacterialinfection remained. A central corneal cicatrix was evident in the areaof previous active infiltrate.

Example 14 Gram Negative Bacterial Corneal Ulceration; Treated withAqueous 0.2% PVP-I in 36% USP Grade DMSO with 3% Hydroxyethylcellulose

This patient was suffering from a bacterial corneal ulceration. In thistype of infection there is often a history of contact lens use, however,this is not a prerequisite. Bacteria is introduced into the eye througha small break in the epithelium and gains foothold to the underlyingstructures. In this patient, the conjunctiva demonstrated diffuseinjection with pyogenic discharge. The cornea demonstrated a central,five-millimeter circular infiltrate with overlying central epithelialdefect. The infiltrate had induced abundant stromalysis and theresultant cornea had thinned by approximately seventy-five percent.There was a two millimeter layered hypopyon in the anterior chamber.Corneal cultures were taken, and Pseudomonas aeruginosa species wasidentified. The patient had tried numerous antibiotics, steroids, oraland topical anti-virals and anti-inflammatories without benefit.Prepared was a composition as disclosed herein using 0.2% PVP-I in 36%DMSO with 3% hydroxyethylcellulose. The patient was treated by applyingthe solution topically to the eye six times daily. Within three days,improvement was noted in and around the eye. The corneal melt had haltedand re-epithelialization had taken place. At one week the hypopyon hadresolved, the conjunctiva cleared and a small central infiltrateremained. By week two, the patient was healed and no active bacterialinfection remained. A central corneal cicatrix was evident in the areaof previous active infiltrate.

Example 15 Fungal Corneal Ulceration; Treated with Aqueous 1.2% PVP-I in45% USP Grade DMSO with 3% Hydroxyethylcellulose

This patient was suffering from a fungal corneal ulceration. In thistype of infection there is often a history of contact lens use, however,this is not a prerequisite. Fungus is introduced into the eye through asmall break in the epithelium and gains foothold to the underlyingstructures. In this patient, the conjunctiva demonstrated diffuseinjection with pyogenic discharge. The cornea contained multifocal,feather-like infiltrates with overlying central epithelial defect. Theinfiltrates had induced minimal stromalysis and the resultant cornea wasnot thinned. There was no hypopyon, however, cell and flare werepresent. Corneal cultures were taken, and Fusarium species wasidentified. The patient had tried numerous antifungals, antibiotics,steroids, oral and topical anti-virals and anti-inflammatories withoutbenefit. Prepared was a composition as disclosed herein using 1.2% PVP-Iin 45% DMSO with 3% hydroxyethylcellulose. The patient was treated byapplying the solution topically to the eye six times daily. Within oneweek, improvement was noted in and around the eye. The cornea had begunthe process of re-epithelialization. At two weeks, corneal infiltratewas resolved, the conjunctiva had cleared and the anterior chamber wasquiet. A central corneal cicatrix was evident in the area of previousactive infiltrate.

Example 16 Acanthamoeba Corneal Ulceration; Treated with Aqueous 0.4%PVP-I in 39% USP Grade DMSO with Hydroxyethyl Cellulose

This patient was suffering from an Acanthamoeba corneal ulceration. Inthis type of infection there is often a history of contact lens use andhome-made contact lens solutions, however, this is not a prerequisite.Acanthamoeba parasites are often introduced into the eye through a smallbreak in the epithelium and gains foothold to the underlying structures.The patient endorses pain out of proportion with examination. In thispatient, the conjunctiva demonstrated diffuse injection. The corneacontained multiple bullous lesions with enlarged corneal nerves. Therewas an overlying epithelial defect and faint ring-shaped infiltrate. Theinfiltrate had induced minimal stromalysis and the resultant cornea wasnot thinned There was no hypopyon, however, cell and flare were present.Corneal cultures were taken, and Acanthamoeba species were identified onnon-nutrient agar with E. coli overlay. The patient had tried numerousanti-amoeboid medicines including chlorhexidine, propamidine,antifungals, antibiotics, steroids, oral and topical anti-virals andanti-inflammatories without benefit. Prepared was a composition asdisclosed herein using 0.4% PVP-I in 39% DMSO with hydroxyethylcellulose. The patient was treated by applying the solution topically tothe eye six times daily. Within one week, improvement was noted in andaround the eye. The corneal had begun the process ofre-epithelialization and the ring ulcer began to lessen in intensity. Attwo weeks the corneal infiltrate was resolved, the conjunctiva clearedand perineuralgia abated. A central corneal cicatrix was evident in thearea of previous active infiltrate.

Example 17 Conjunctival Squamous Papilloma; Treated with 1.9% PVP-I in46% USP Grade DMSO with 3% Hydroxyethylcellulose

This patient was suffering from a conjunctival papilloma. In this typeof dysplasia conjunctival cells demonstrate an exophytic orcauliflower-like pattern. They may also grow in a finger-like patternand are often lobulated with vascular cores. The process is oftenassociated with UV exposure, smoking, or human papilloma virus. In thispatient, the conjunctiva demonstrated an exophytic mass with apedunculated base, frond-like growth and vascular core. Conjunctivalbiopsy was taken and pathology report confirmed the diagnosis. Thepatient had tried numerous topical chemotherapeutic agents such asmitomycin and interferon. Topical anti-inflammatories were alsoadministered. Eventual excision with cryotherapy was performed, however,the lesion recurred. Prepared was a composition as disclosed hereinusing 1.9% PVP-I in 46% DMSO with 3% hydroxyethylcellulose. The patientwas treated by applying the solution topically to the eye four timesdaily. Within one month, improvement was noted in the eye. Theconjunctival lesion had begun to involute and diminish surface area. Attwo months there had been complete regression of the lesion with healthyappearing underlying conjunctiva. Post-treatment biopsy in the affectedarea was negative.

Example 18 Corneal Squamous Papilloma; Treated with 0.8% PVP-I in 43%USP Grade DMSO 3% Hydroxyethylcellulose

This patient was suffering from a corneal squamous papilloma. In thistype of dysplasia corneal cells demonstrate an exophytic orcauliflower-like pattern. They may also grow in a finger-like patternand are often lobulated with vascular cores. The process is oftenassociated with UV exposure, smoking, or human papilloma virus. In thispatient, the cornea demonstrated an exophytic mass with a pedunculatedbase, frond-like growth and vascular core. Corneal biopsy was taken andpathology report confirmed the diagnosis. The patient had tried numeroustopical chemotherapeutic agents such as mitomycin and interferon.Topical anti-inflammatories were also administered. Eventual excisionwith cryotherapy was performed, however, the lesion recurred. Preparedwas a composition as disclosed herein using 0.8% PVP-I in 43% DMSO with3% hydroxyethylcellulose. The patient was treated by applying thesolution topically to the eye four times daily. Within one month,improvement was noted in the eye. The corneal lesion had begun toinvolute and diminish in surface area. At two months there had beencomplete regression of the lesion with healthy appearing corneal tissue.Post-treatment biopsy in the affected area was negative.

Example 19 Eyelid Squamous Papilloma; Treated with 1.7% PVP-I in 47% USPGrade DMSO with 3% Hydroxyethylcellulose

This patient was suffering from an eyelid squamous papilloma. In thistype of dysplasia, cells demonstrate an exophytic or cauliflower-likepattern. They may also grow in a finger-like pattern and are oftenlobulated with vascular cores. The process is often associated with UVexposure, smoking, or human papilloma virus. In this patient, the eyelidlamellae demonstrated an exophytic mass with a pedunculated base,frond-like growth and vascular core. Eyelid biopsy was taken andpathology report confirmed the diagnosis. The patient had tried numeroustopical chemotherapeutic agents such as mitomycin and interferon.Topical anti-inflammatories were also administered. Eventual excisionwith cryotherapy was performed, however, the lesion recurred. Preparedwas a composition as disclosed herein using 1.7% PVP-I in 47% DMSO with3% hydroxyethylcellulose. The patient was treated by applying thesolution topically to the eye four times daily. Within one month,improvement was noted. The eyelid lesion had begun to involute anddiminish in surface area. At two months there had been completeregression of the lesion with healthy appearing eyelid tissues andstructures.

Example 20 Eyelid Verrucae; Treated with 0.1% PVP-I in 43% USP GradeDMSO 3% Hydroxyethylcellulose

This patient was suffering from eyelid verrucae. This type of eyelidgrowth usually commences with gray or tan papules that progress tohyperkeratotic lesions with a papillomatous surface. The process isoften associated with human papilloma virus infection of the epitheliallayers. In this patient, the superior eyelid demonstrated a solid whitegrowth with a papillomatous surface. Eyelid biopsy was taken andpathology report confirmed the diagnosis. The patient had tried numeroustopical agents without benefit. Cryotherapy was eventually performed,however, the lesion recurred. Prepared was a composition as disclosedherein using 0.1% PVP-I in 43%

DMSO with polypropylene glycol. The patient was treated by applying thesolution topically to the eyelid structures four times daily. Within twoweeks, improvement was noted. The lesion had begun to involute anddiminish in surface area. At one month there had been completeregression of the lesion with healthy appearing eyelid tissues and skin.

Example 21 Eyelid Molluscum Contagiosum; Treated with 0.9% PVP-I in 39%USP Grade DMSO with 3% Hydroxyethylcellulose

This patient was suffering from an eyelid associated molluscumcontagiosum. This type of eyelid infection usually demonstrates fleshcolored, dome-shaped pearly papules with dimpled centers. The process isoften associated with pox virus infection of the epithelial layers. Inthis patient, the upper eyelid and lid margin demonstrated multipleflesh colored papules with dimpled centers. The patient had triednumerous topical agents without benefit including salicylic acid andimiquimod. Cryotherapy with excision was eventually performed, however,the lesions recurred. Prepared was a composition as disclosed hereinusing 0.9% PVP-I in 39% DMSO with hydroxyethyl cellulose. The patientwas treated by applying the solution topically to the eyelid and marginstructures four times daily. Within two weeks, improvement was noted.The lesions had begun to involute and diminish in surface area. At onemonth there had been complete regression of the lesions with healthyappearing eyelid tissues and lamellae.

Example 22 Eyelid Antisepsis Prior to Cataract Surgery; Treated with0.2% PVP-I in 44% USP Grade DMSO 3% Hydroxyethylcellulose

This patient was suffering from an anterior and posterior blepharitisprior to cataract surgery. Numerous ophthalmic studies have implicatedbacteria that populate the eyelids and conjunctiva as those beingresponsible for post-operative infectious endophthalmitis. It istherefore routine to attempt to sterilize these surfaces prior tocommencing said procedure. In this patient, the posterior lid margindemonstrated meibomian gland thickening, keratinization, fatsaponification, and dilated, telangectatic lid vessels. The anterior lidmargin also demonstrated scurf and bacterial overgrowth. The patient hadtried numerous topical agents to sterilize the ocular surface includingtopical antibiotics and antiseptics without benefit. Prepared was acomposition as disclosed herein using 0.2% PVP-I in 44% DMSO with 3%hydroxyethylcellulose The patient was treated by applying the solutiontopically to the eye and eyelid three times daily commencing 3 daysprior to the procedure. On the day of the procedure, conjunctivalcultures were taken and demonstrated no growth. The patient underwent asuccessful procedure and had an uneventful post-operative course.

Example 23 Eyelid Antisepsis Prior to Intravitreal Injection; Treatedwith 1.4% PVP-I in 32% USP Grade DMSO with 3% Hydroxyethylcellulose

This patient was suffering from an anterior and posterior blepharitisprior to intravitreal injection. Numerous ophthalmic studies haveimplicated bacteria that populate the eyelids and conjunctiva as thosebeing responsible for post-injection infectious endophthalmitis. It istherefore routine to attempt to sterilize these surfaces prior tocommencing said procedure. In this patient, the posterior lid margindemonstrated meibomian gland thickening, keratinization, fatsaponification, and dilated, telangectatic lid vessels. The anterior lidmargin also demonstrated scurf and bacterial overgrowth. The patient hadtried numerous topical agents to sterilize the ocular surface includingtopical antibiotics and antiseptics without benefit. Prepared was acomposition as disclosed herein using 1.4% PVP-I in 32% DMSO with 3%hydroxyethylcellulose. The patient was treated by applying the solutiontopically to the eye and eyelid three times daily commencing 3 daysprior to the procedure. On the day of the procedure, conjunctivalcultures were taken and demonstrated no growth. The patient underwent asuccessful injection and had an uneventful post-operative course.

The Examples and description provided herein are not intended as, andare not, limiting to the breadth of protection afforded within the fullscope and spirit of the invention as described.

1. A stable ophthalmically acceptable gel composition comprising 0.15%to 1.5% povidone-iodine (PVP-I); 30% to 97% dimethyl sulfoxide (DMSO);2.5% to 5% hydroxyethylcellulose; and water or isotonic co-solventwherein, the composition is a topical ophthalmic gel, free of additionalanti-inflammatory drug.
 2. The composition of claim 1, comprising 0.15%to 1.0% PVP-I.
 3. The composition of claim 1, comprising 0.25% to 0.5%PVP-I
 4. The composition of claim 1, comprising about 0.25% PVP-I. 5.The composition of claim 1, comprising 30% to 70% DMSO.
 6. Thecomposition of claim 1, comprising 40% to 49% DMSO.
 7. The compositionof claim 1, comprising 44% DMSO.
 8. The composition of claim 1,comprising 2.5% to 4% gelling agent.
 9. The composition of claim 1comprising 3% gelling agent.
 10. The composition of claim 1, comprising:0.25% PVP-I; 44% DMSO; 3% hydroxyethylcellulose; and a co-solvent, andwherein said composition is steroid-free and NSAID-free.
 11. Thecomposition of claim 10, wherein the co-solvent is water or aqueousisotonic solution.
 12. A stable gel composition of claim 1, wherein, thecomposition is a topical ophthalmic preparation wherein each ingredientis ophthalmically acceptable, and said ophthalmic gel compositionretains at least 85% of titratable iodine in povidone-iodine startingmaterial for at least 72 hours.
 13. The stable gel composition of claim12 wherein the composition retains at least 85% of titratable iodine inpovidone-iodine starting material for at least one month.
 14. The stablegel composition of claim 12 wherein the composition retains at least 85%of titratable iodine in povidone-iodine starting material for up to 12months.
 15. A method of treating an infectious condition of the eye oreyelid, said method comprising the step of: applying an effective amountof a stable, topical ophthalmic gel composition of claim 1 to a site ofthe infection as needed to reduce or eliminate the infection.
 16. Themethod of claim 15 wherein said infectious condition is selected fromthe group consisting of blepharitis, conjunctivitis, corneal ulcer,bacterial keratitis, viral keratitis, post-operative endophthalmitis,and endophthalmitis after intravitreal or intracameral injection. 17.The method of claim 16, wherein the infectious condition is caused by orassociated with one or more infectious agents selected from the groupconsisting of bacteria, demodex, fungus or yeast, and virus.
 18. Themethod of claim 15 wherein the condition is blepharitis,blapharoconjunctivitis, conjunctivitis, keratitis or infectious cornealulcer.
 19. The method of claim 15, wherein the infectious agent is avirus.
 20. The method of claim 15, wherein the infectious agent isdemodex.